Melphalan
Melphalan (Wikipedia entry) Mechanism [[#pmid16091744|Gomez-Bougie et al. (2005)]] report that melphalan-induced apoptosis in multiple myeloma cells is associated with a cleavage of Mcl-1 and Bim and a decrease in the Mcl-1/Bim complex. In-vivo studies [[#pmid16781199|Souliotis et al. (2006)]] note that preferential DNA repair of melphalan-induced damage in human genes is greatly affected by the local chromatin structure. In-vitro studies [[#pmid17324338|Yang et al. (2007)]] carried out an experimental study enhancing the chemosensitivity of multiple myeloma to melphalan by using a tissue-specific APE1-silencing RNA expression vector. [[#pmid10658534|Pinguet et al. (1999)]] studied the influence of the schedule of exposure on the cytotoxic effect of melphalan on human 8226 cells. [[#pmid18024399|Dimopoulos et al. (2007)]] use melphalan-induced DNA damage in vitro as a predictor for clinical outcome in multiple myeloma. Resistance [[#pmid19447222|Kühne et al. (2009)]] analysed resistance to melphalan in MDR1 overexpressing tumor cell lines, using influx and efflux transport as determinants. [[#pmid12070031|Spanswick et al. (2002)]] examined the repair of DNA interstrand crosslinks as a mechanism of clinical resistance to melphalan in multiple myeloma. [[#pmid16569345|Greco et al. (2006)]] studied the role of PDGF-BB, noting that c-MYC deregulation is involved in melphalan resistance for myeloma. [[#pmid15802532|Chen et al. (2005)]] note that the FA/BRCA pathway is involved in melphalan-induced DNA interstrand cross-link repair and accounts for melphalan resistance in multiple myeloma cells. [[#pmid14633719|Hazlehurst et al. (2003)]] performed genotypic and phenotypic comparisons of de novo and acquired melphalan resistance in an isogenic multiple myeloma cell line model. [[#pmid12017294|Efferth et al. (2002)]] note that IL-6 affects melphalan-induced DNA damage and repair in human multiple myeloma cells. [[#pmid10940652|Harada et al. (2000)]] report a down-regulation of CD98 in melphalan-resistant myeloma cells with reduced drug uptake. [[#pmid7513621|Mulcahy et al. (1994)]] report an up-regulation of gamma-glutamylcysteine synthetase activity in melphalan-resistant human multiple myeloma cells expressing increased glutathione levels. [[#pmid9664139|Gazitt et al. (1998)]] note that Bcl-2 overexpression is associated with resistance to dexamethasone, but not melphalan, in multiple myeloma cells. Enhancing Arsenic trioxide [[#pmid17255285|Trudel et al. (2007)]] report that the Bcl-2 family protein inhibitor, ABT-737 shows a synergistic effect with dexamethasone and melphalan. Regimens *ABCM: Doxorubicin (Adriamycin), Carmustine (BCNU), Cyclophosphamide and Melphalan *M: Melphalan *MP: Melphalan and Prednisone *MPR: Melphalan, Prednisone and Lenalidomide (Revlimid) *MPT: Melphalan, Prednisone and Thalidomide *VBMCP: Vincristine, Carmustine (BCNU), Melphalan, Cyclophosphamide and Methylprednisolone *VMCP: Vincristine, Melphalan, Cyclophosphamide and Methylprednisolone Other combinations Clinical studies Bergsagel (2003) notes the importance of melphalan in myeloma treatment, despite being 40 years old. Similarly Musto and D'Auria (2007) review the old and new uses of this still important drug. [[#pmid17627453|Falco et al. (2007)]] review melphalan's role in the management of patients with multiple myeloma. [[#pmid17680022|Nath et al. (2007)]] report on the pharmacokinetics of melphalan in myeloma patients undergoing an autograft. [[#pmid9855245|Schey et al. (1998)]] note that the variable absorption of melphalan from the gastrointestinal tract results in response rates between 40 and 60%. Intravenous intermediate dose melphalan and dexamethasone was found to maintain an improved response rate compared to oral melphalan and prednisolone while reducing toxicity. Initial therapy Relapsed or refractory therapy Complications Reduced stem cell mobilisation [[#pmid12161361|Boccadoro et al. (2002)]] report that oral melphalan at diagnosis hampers adequate collection of peripheral blood progenitor cells in multiple myeloma. [[#pmid11488852|Kazmi et al. (2001)]] also report the effects of prior induction therapy with melphalan on subsequent peripheral blood progenitor cell transplantation for myeloma. [[#pmid10618687|Knudsen et al. (1999)]] report reduced bone marrow stem cell pool and progenitor mobilisation in multiple myeloma after melphalan treatment. Other [[#pmid7825976|Kergueris et al. (1994)]] consider influence of renal function on the pharmacokinetics of high-dose melphalan in adults. [[#pmid10578165|Schuh et al. (1999)]] report a case where encephalopathy complicated the use of high-dose melphalan. References